Porphyromonas gingivalis is a periodontal pathogen that initially colonizes the oral cavity by adhering to S. gordonii via interaction of the minor fimbrial antigen Mfa1 with a specific motif of the streptococcal SspB protein designated BAR. Synthetic peptides which mimic BAR function are potent inhibitors of P. gingivalis adherence/biofilm formation, but are both costly to synthesize and active compounds are susceptible to proteolysis. Thus rationally-designed, stable small molecule peptidomimetics of BAR that inhibit P. gingivalis adherence to S. gordonii represents a potential therapy in maintaining oral health. A small-molecule click chemistry strategy is being developed whereby the azide-bearing and acetylenic partners constitute trisubstituted oxazole and diaminoaryl frameworks respectively. Seventeen azide-bearing compounds were synthesized as mimics of the NITVK motif of BAR. Two compounds partially inhibited planktonic growth of P. gingivalis and several were found active at varying levels in inhibition of adherence to streptococci. Our route to the azide-bearing trisubstituted oxazole scaffolds employs a unique strategy starting with an array of nonsymmetrical acyloins and culminates with the azido group being strategically positioned. Though synthetically more straightforward, the preparative routes to the acetylenic click partners employ an array of ethynyl diamino aryl components. The synthesis of the heterocyclic click partners and the evaluation of their inhibitory efficacy in the BAR assays will be presented.

Design and synthesis of peptidomimetic inhibitors of <i>Porphyromonas gingivalis</i> biofilm formation

248th National Meeting (2014)

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Design and synthesis of peptidomimetic inhibitors of Porphyromonas gingivalis biofilm formation